2-237340988-G-A

Position:

chr2-237340988-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004369.4(COL6A3):c.7928C>T(p.Ala2643Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,164 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2643A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0045 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 12 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.82

Variant links:

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00923264).

BP6

Variant 2-237340988-G-A is Benign according to our data. Variant chr2-237340988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237340988-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0045 (685/152288) while in subpopulation AFR AF= 0.0136 (565/41560). AF 95% confidence interval is 0.0127. There are 8 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.7928C>T	p.Ala2643Val	missense_variant	38/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.7310C>T	p.Ala2437Val	missense_variant	37/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.6107C>T	p.Ala2036Val	missense_variant	35/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.7928C>T	p.Ala2643Val	missense_variant	38/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.00444

AC:

676

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00192

AC:

483

AN:

250964

Hom.:

AF XY:

0.00155

AC XY:

210

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00135

AC:

1977

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

909

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00450

AC:

685

AN:

152288

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00475

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00222

AC:

269

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	COL6A3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2015	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.28

.;T;.;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.87

D;D;D;D;.

MetaRNN

Benign

0.0092

T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.2

.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.041

D;T;T;T;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

0.52

P;D;.;.;P

Vest4

0.22

MVP

0.81

MPC

0.15

ClinPred

0.014

GERP RS

-3.2

Varity_R

0.075

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over